leukotriene-c4 and Bronchopulmonary-Sequestration

The interference of the 5-lipoxygenase inhibitor, BW B70C ((E)-N-(3-[3-(4-fluorophenoxy)phenyl]-1(R,S)-methyl prop-2-enyl)-N-hydroxyurea), with Escherichia coli lipopolysaccharide (endotoxin)-induced lung leucocyte sequestration and microvascular albumin exchanges was evaluated in the anaesthetised guinea-pig using radioactive tracers, in parallel to the effects on cell counts in the broncho-alveolar lavage fluid, blood tumour necrosis factor (TNF-alpha) content, secretion of phospholipase A2 and synthesis of leukotriene C4 by alveolar macrophages. Intravenous injections of 0.1 or 1 mg/kg endotoxin induced lung leucocyte sequestration but only the higher dose induced an increase in albumin microvascular exchanges and the infiltration of leucocytes towards the airway lumen. Leukotriene B4, a potential mediator of the 5-lipoxygenase-dependent endotoxin effects, induced a rapid and transient lung leucocyte sequestration and leucopenia associated with a more progressive increase in microvascular exchanges. The 5-lipoxygenase inhibitor, BW B70C, injected i.p. (30 mg/kg) prevented leukotriene C4 synthesis by alveolar macrophages and reduced leucocyte migration to the airways lumen as well as albumin microvascular leakage but did not affect the endotoxin-induced increase in the blood level of TNF-alpha and of secreted phospholipase A2. However, BW B70C failed to modify vascular leucocyte margination induced by 1 mg/kg endotoxin, suggesting that, apart from a role of 5-lipoxygenase, alternative pathways operate in response to endotoxin in guinea-pig.

Topics: Animals; Blood Proteins; Bronchoalveolar Lavage Fluid; Bronchopulmonary Sequestration; Cell Count; Cell Separation; Dose-Response Relationship, Drug; Drug Interactions; Escherichia coli; Guinea Pigs; Hydroxylamines; Hydroxyurea; Injections, Intravenous; Isotope Labeling; Leukocytes; Leukopenia; Leukotriene B4; Leukotriene C4; Lipopolysaccharides; Lipoxygenase Inhibitors; Lung; Macrophage Activation; Macrophages, Alveolar; Methylurea Compounds; Phospholipases A; Phospholipases A2; Radioimmunoassay; Serum Albumin; Tumor Necrosis Factor-alpha